1. Field of the Invention
The present invention concerns antitumor compounds. More particularly, the invention provides novel thiolated taxane derivatives which are preferably linked to colloidial metal particles, such as gold nanoparticles, and used as antitumor agents, and which can be linked to gold nanoparticles to provide stable, extended delivery targeted drug compositions.
2. Background of the Invention
Cancer chemotherapy today still depends largely on cytotoxic agents that kill cancer cells by mechanisms such as disruption of the mitotic spindle or interacting with DNA. These therapies are effective in many cases, and have resulted in decreased cancer mortality, but they suffer from the major defect that they are relatively non-selective, and affect normal cells to some extent as well exerting their desired effect on cancer cells. The deleterious effects of the non-selectivity of these agents, such as paclitaxel, doxorubicin, vinblastine, bleomycin, and many other agents, could largely be abrogated if the drugs could be targeted directly to the tumor.
One of the most effective current clinical agents is Paclitaxel (Taxol™) a depiction of which is presented in FIG. 1. This compound is a natural product extracted from the bark of Pacific yew trees, Taxus brevifolia. It has been shown to have excellent antitumor activity in in vivo animal models, and studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis (Schiff, P B, Fant, J, Horwitz, S B. “Promotion of microtubule assembly in vitro by taxol.” Nature 1979 277:665-667). Paclitaxel has been approved for the treatment of ovarian and breast cancers, as well as Kaposi's sarcoma; and studies involving colon, and lung cancers have shown promising results. The results of paclitaxel clinical studies are reviewed in Nowak, A. K.; Wilcken, N. R. C.; Stockler, M. R.; Hamilton, A.; Ghersi, D. Systematic review of taxane-containing versus non-taxane-containing regimens for adjuvant and neoadjuvant treatment of early breast cancer. The Lancet 2004, 5, 372-830; in Crown, J.; O'Leary, M.; Ooi, W.-S. Docetaxel and paclitaxel in the treatment of breast cancer: A review of clinical experience. The Oncologist 2004, 9, 24-32; and in Brown, D. T., Preclinical and clinical studies of the taxanes. In Taxus: The genus Taxus, Itokawa, H., Lee, K. H., Eds.; Taylor and Francis: London, 2003; Vol. pp 387-435.
Various methods have been developed for the targeting of paclitaxel to tumors. These include the use of antibodies (Ojima, I. Guided Molecular Missiles for Tumor-Targeting Chemotherapy-Case Studies Using the Second-Generation Taxoids as Warheads. Acc Chem Res 2007), the use of peptides (Kumar, S K, Williams, S A, Isaacs, J T, Denmeade, S R, Khan, S R. Modulating paclitaxel bioavailability for targeting prostate cancer. Bioorg & Med Chem 2007 15:4973-4984), and the use of folic acid (Lee, J W, Lu, J Y, Low, P S, Fuchs, P L. Synthesis and Evaluation of Taxol-Folic Acid Conjugates as Targeted Antineoplastics. Bioorg Med Chem 2002 10:2397-2414) and the use of DHA (Bradley, M O, Swindell, C S, Anthony, F H, Witman, P A, Devanesan, P, Webb, N L, Baker, S D, Wolff, A C, Donehower, R C. Tumor Targeting by Conjugation of DHA to Paclitaxel. J Controlled Release 2001 74(1-3):233-236). The subject of improved drug delivery methods for paclitaxel has been discussed in a recent review (Ganesh, T. Improved biochemical strategies for targeted delivery of taxoids. Bioorg & Med Chem 2007 15:3597-3623), and prodrug strategies for paclitaxel delivery have also been reviewed (Skwarczynski, M, Hayashi, Y, Kiso, Y. Paclitaxel Prodrugs: Toward Smarter Delivery of Anticancer Agents. J Med Chem 2006 49:7253-7269).
The combination of gold nanoparticles with tumor necrosis factor (TNFα) targets the nanoparticles to tumors and provides a therapeutic effect. This effect is enhanced when paclitaxel is also linked to the nanoparticles (Paciotti, G F, Kingston, D G I, Tamarkin, L. Colloidal Gold Nanoparticles: A Novel Nanoparticle Platform for Developing Multifunctional Tumor-targeted Drug Delivery Vectors. Drug Devel Res 2006 67:47-54). Unfortunately, the currently available paclitaxel derivatives do not give the full therapeutic effect that is desired. It would therefore be beneficial to develop paclitaxel derivatives which have the desired properties for combining with gold nanoparticles, and which also exhibit the full desired therapeutic effect.